tbuckley/cabot-search huggingface dataset:
Abstract 3383: Liquid biopsy for PDL-1 status by analysis of cfRNA: Clinical data from a large community practice
Authors: Lowell L. Hart, Magali Van den Bergh
Journal: Cancer Research (2023)

Abstract PD-L1 testing via immunochemistry has become a widely used tool to predict response to immune checkpoint inhibitor (ICI) therapy in many tumor types. However this marker can be expressed heterogeneously, and can vary with time, treatment effects, and local factors including cytokine expression. Gene expression profiles of immunologically active genes are currently being studied to more accurately predict response to ICI treatment. To evaluate a potentially more straightforward way to accomplish this, we utilized an assay of cfRNA in plasma for PD-L1, utilizing a real-time PCR based assay (Circulogene, Inc, Birmingham, AL). The demonstrated limit of detection for PD-L1 RNA was 1 copy/ul. Results were reported as either not detected, or low at over 1%, or high at over 50%. We used the PCR 30th percentile Ct value corresponding to a tissue IHC PD-L1 of&amp;gt;50%, and the 66th percentile Ct value corresponding to a tissue PD-L1 expression of &amp;gt;1%. We then collected data on over 400 patients over a two year period at a large community oncology practice and at a university clinic (Florida Cancer Specialists and Atrium Health/Wake Forest-Baptist Comprehensive Cancer Center) who had a clinical necessity for molecular testing in a commercially available setting with a CLIA certified lab. In some cases the corresponding tissue PD-L1 testing was also available, and may have been either positive or negative.To date 41 patients have been found to have high levels of cfRNA for PD-L1. Their clinical course has been analyzed using the electronic medical record. Some patients have received standard of care therapy, and some have been given CPI therapy with or without chemotherapy, if the attending oncologist felt this to be the best palliative option. These include tumors such as CRPC, metastatic low grade neuroendocrine carcinoma and HR+ metastatic breast carcinoma, that have rarely been treated successfully with CPI therapy. Tumor types - all are stage IV solid tumor patients: 19 NSCLC, 7 breast carcinoma, 3 colorectal cancer, 3 castrate resistant prostate carcinoma, 9 other tumor types.Data collection for tumor response or clinical benefit on the 41 patients is ongoing and will be presented at the meeting, and compared to published CPI response data using standard tissue IHC testing. Citation Format: Lowell L. Hart, Magali Van den Bergh. Liquid biopsy for PDL-1 status by analysis of cfRNA: Clinical data from a large community practice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3383.
Abstract 537: Validating USP27X as a drug target in lung cancer
Authors: Shamshad Alam, Amanda Zunic, Swati Venkat, Michael E Feigin, Boyko Atanassov
Journal: Cancer Research (2023)

Abstract Over the past two decades, tremendous efforts have been dedicated to developing and improving receptor tyrosine kinase (RTK) targeted therapies to combat the development and progression of different cancers. Despite the significant progress made, these therapies are not durable: not all patients respond to treatment, and primary or acquired resistances are common. Interestingly, however, while RTK-targeted therapies have no effect on resistant lung cancer cell lines, si/shRNA-mediated RTK depletion or combined treatments that affect RTK protein levels profoundly impact the growth and survival of these cells, indicating that RTKs are still critical for their proliferation. Thus, strategies to target RTK protein levels hold promise as an option for treating RTK-driven cancers. In our recent studies, we discovered that ubiquitin-specific protease 27X (USP27X) functions are crucial for properly recycling and maintaining EGFR steady-state levels in lung cancer cells. Ablation of USP27X leads to a severe decrease of EGFR steady levels, inhibition of xenograft tumor growth, and sensitization of lung cancer cell lines to targeted therapy. To fully understand the in vivo functions of USP27X in EGFR regulation and lung carcinogenesis, we created a new mouse line carrying a conditional Usp27X allele and introduced this allele into the well-established and clinically relevant EGFRL858R mouse lung cancer model. Ongoing studies will determine whether USP27X can be a critical therapeutic in EGFR-driven lung cancer. Citation Format: Shamshad Alam, Amanda Zunic, Swati Venkat, Michael E Feigin, Boyko Atanassov. Validating USP27X as a drug target in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 537.
Abstract 3093: Synthesis and bioevaluation of LAT-1 efflux agonists for the treatment of pancreatic cancers
Authors: Holly Moots, Houssine Ikhlef, Vandana Sekhar, Otto Phanstiel
Journal: Cancer Research (2023)

Abstract The purpose of this report is to describe the discovery and development of the world’s first L-type amino acid transporter 1 (LAT-1) efflux agonist. LAT-1 is used for the import of amino acid substrates (leucine, phenylalanine, and methionine) and LAT-1 expression has been showed to be increased in pancreatic ductal adenocarcinoma (PDAC) cells. LAT-1 is a promising target for the treatment of rapidly growing cancers, such as PDAC, in part, due to its key role in methionine import. Methionine is required for various cellular processes, including the generation of S-adenosylmethionine (SAM) and the maintenance of intracellular polyamine pools, which are essential for PDAC growth. Indeed, the biosynthesis of the higher polyamines (spermidine and spermine) requires the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine (dc-SAM), illustrating the molecular connection between methionine and polyamine pools. LAT-1 inhibition, such as with the known LAT-1 inhibitor JPH203, has shown efficacy in suppressing tumor growth in pancreatic cancer cell lines. While the early pre-clinical data is promising, competitive inhibitors of LAT-1 may have limited potency in the presence of high extracellular levels of LAT-1 substrates. In contrast, LAT-1 efflux agonists are insensitive to extracellular LAT-1 substrates. These novel compounds reverse the flow of substrates through LAT-1, effectively depleting cells of key intracellular amino acids, rather than blocking the import of extracellular substrates like methionine. The chiral piperazine (1), our lead efflux agonist, was discovered by a high throughput screen and was shown to deplete intracellular methionine, leucine and phenylalanine pools by LC-MS as well as decrease the synthesis of the higher polyamines (spermidine and spermine), a process which is reliant upon methionine as a precursor. A structure activity relationship (SAR) analysis of the four possible diastereomers of 1 was performed. The performance of these diastereomers and other derivatives were evaluated by LC-MS, HPLC, and Western blot. These molecules were shown to increase 3H-leucine efflux, decrease intracellular polyamine, SAM, and S-adenosylhomocysteine (SAH) levels, decrease phosphatidylethanolamine levels and induce the autophagic marker LC3-II. In summary, this novel method of methionine restriction allows one to alter intracellular methionine levels in a dose-dependent manner and provides a novel way to control pancreatic cancer cell growth. Citation Format: Holly Moots, Houssine Ikhlef, Vandana Sekhar, Otto Phanstiel. Synthesis and bioevaluation of LAT-1 efflux agonists for the treatment of pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3093.
Abstract 2092: Consensus analysis of associated target-biomarker pairs in cancers
Authors: Sumin Jeong, Yuna Park, Eunah Jeong, Sukjoon Yoon
Journal: Cancer Research (2023)

Abstract The heterogeneity of cancers limits the reproducibility of target-biomarker relationships in diverse cohorts or sample groups. Here, we carried out consensus analyses of associated data pairs to improve the consistency (reproducibility) of prognostic power of biomarkers and anticancer efficacy of targets. All of RNA expression, patient survival, CRIRSPR/shRNA screening data were integrated from TCGA, GDSC and CCLE datasets. While &amp;gt;90% of prognostic RNA expression found in given sample sets were not reproduced (i.e., not significant) in other test sets, those hits exhibiting consensus prognostic powers in diverse subtypes or lineages, were more significant in test sets than non-consensus hits. In the analysis of the association between CRISPR knockout and RNA expression data, the lineage consensus of the association increased the reproducibility in the validation using sh/siRNA knockdown and qPCR data. Further experimental validations reveal that ITGAV is an effective anticancer target in diverse lineages, significantly associated with prognostic RNA expression of several consensus biomarker genes. In conclusion, the consensus analysis was useful to prioritize reproducible targets and biomarkers from omics data. It has been implemented in Q-omics software (http://qomics.io) for general cancer research. Citation Format: Sumin Jeong, Yuna Park, Eunah Jeong, Sukjoon Yoon. Consensus analysis of associated target-biomarker pairs in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2092.
Abstract 5605: Ambient storage and stabilization of proteins and cell-free nucleic acids in whole blood samples
Authors: Jing Li, Lisa Bartron, Jordan LaRue, Sama Mehta, Nicholas M. George
Journal: Cancer Research (2023)

Abstract Introduction: Highly anticipated advancements in biotechnology and instrumentation now allows for simultaneous detection of multiple biomarkers. This is accelerating the cancer research field towards the development of multianalyte-based in vitro diagnostic tests for early detection and/or monitoring of cancer. These multianalyte liquid biopsy tests are often based on detection of cancer-related proteins and/or tumor-specific genomic and transcriptomic changes (circulating cell-free nucleic acids) in plasma. A specialized and proprietary stabilization reagent has been developed for use in a blood collection tube with the capability to simultaneously stabilize protein biomarkers of interest and cell-free nucleic acids. Methods: Blood samples from self-proclaimed healthy donors were drawn into evacuated blood collection tubes containing a new stabilization reagent and stored at room temperature. Plasma was isolated using a general double-spin protocol (1800 × g for 15 min and 2800 × g for 15 min) and frozen at -80 °C until use. Plasma levels of proteins of interest including cancer markers and immuno-oncology checkpoint markers were measured by Ella Simple Plex Assays (Bio-Techne) and Luminex xMAP® Technology Assays (Bio-Techne, samples tested by LuminexPLORE Lab). Total cell-free nucleic acids were isolated using the QIAamp Circulating Nucleic Acid Kit and the resultant cfDNA or cfRNA was analyzed with fluorometric-based assay (quantitative) and Bioanalyzer/Tapestation (qualitative). Results: Compared with blood samples collected in EDTA and ACD-A tubes, the new stabilization reagent maintained the draw time levels of plasma proteins of interest such as TGF-β1, MMP-9, IL-8/CXCL8, CCL5/RANTES, Granzyme B, CEA and PD-L1 for up to 5 days of room temperature storage in whole blood. The reagent also effectively maintained draw time levels of plasma cell-free nucleic acids to near draw time levels. In addition, the new reagent also minimized in vitro hemolysis during room temperature storage. Conclusion: This new and breakthrough stabilization reagent simultaneously maintains the draw time levels of proteins of interest and cell-free nucleic acids for an extended period of time in whole blood. It provides cancer researchers and clinical assay developers confidence in blood sample integrity and flexibility in sample storage, transport, and processing at ambient temperature for multianalyte analysis or multiomics profiling. Citation Format: Jing Li, Lisa Bartron, Jordan LaRue, Sama Mehta, Nicholas M. George. Ambient storage and stabilization of proteins and cell-free nucleic acids in whole blood samples. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5605.
Abstract 1083: MEKi and SOS1i as a combination treatment option for KRAS mutant endometrial cancer
Authors: Kaja Kostyrko, Melanie Hinkel, Marco H. Hofmann, Francesca Trapani
Journal: Cancer Research (2023)

Abstract Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting in over 75,000 deaths per year worldwide. Despite recent advances in medical oncology research, chemo- and radiotherapy are still the standard of care treatments for recurrent or metastatic EC and prognosis for these patients remains poor, with median survival rates of less than one year. Approximately 15-30% of the more common type I EC harbors oncogenic KRAS mutations, which have been linked to disease progression. Preclinical studies have shown that MEK inhibitors exhibit strong anti-tumor activity in KRAS mutant EC models. In the clinical setting however, MEKi monotherapy has proven unsuccessful in KRAS mutant EC patients, suggesting that combinations with other targeted agents may be needed to achieve increased signaling modulation and enhanced therapeutic activity. As suggested by our previous work in KRAS mutant lung, colorectal and pancreatic cancer, the combined inhibition of MEK and SOS1 may overcome adaptive resistance to MEKi by blocking SOS1-mediated reactivation of MAPK signaling. We evaluated whether this hypothesis can also be applied in the context of EC. Here we treated preclinical models of EC with a combination of clinically relevant doses of a MEKi (trametinib) and BI-3406, a potent and selective orally bioavailable SOS1 inhibitor. Treatment of KRAS mutant EC cells resulted in decreased activity of the KRAS-MAPK pathway, as measured by ERK phosphorylation. This effect was further enhanced by co-treatment with BI-3406. In vivo, the combination of MEKi with SOS1i synergistically decreased tumor growth in two KRAS G12D mutant orthotopic patient-derived xenograft models of EC. The anti-tumor effect of the combination was comparable to the effect of paclitaxel, the standard of care treatment in EC. This suggests that the combination of MEKi with SOS1i may be a potential therapeutic approach for the treatment of EC patients with tumors harboring KRAS mutations. Citation Format: Kaja Kostyrko, Melanie Hinkel, Marco H. Hofmann, Francesca Trapani. MEKi and SOS1i as a combination treatment option for KRAS mutant endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1083.
Abstract 1328: Building a 3D co-culture model for metastatic pancreatic ductal cancer using Curiochips microphysiological system
Authors: Sumin Kim, Yeongmin Choi, Jihye Baek, Bharti Garg, Jan Pencik, Andrew M. Lowy, Herve Tiriac, Sanghee Yoo
Journal: Cancer Research (2023)

Abstract Despite the use of multi-agent conventional chemotherapy regimens, metastatic pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors with a 5-year survival of 9%. PDAC is characterized by a complex tumor microenvironment with multilayered interplay between neoplastic and stromal cells and the natural extracellular matrix (ECM). To date, models that recapitulate the complexity of these features are only partially reproduced ex vivo and lack the capacity to recreate PDAC tumor microenvironment physiology, fluid flow and the ECM architecture. To address these issues, we developed Curiochips MPS platform for metastatic PDAC on-a-chip. To replicate an accurate PDAC complex tumor microenvironment, we investigated human pancreatic cancer cell lines with/without SMAD4 mutation as a test model. SMAD4 is among the most frequently altered genes in PDAC and its mutation accelerates pancreatic cancer cell migration. To tailor cell-ECM interactions and recreate natural biochemical environment of tumors, we examined various ECM conditions. ECM substitutes such as type I collagen and fibrin gel offer mechanical properties to closely mimic the tumor ECM. We accessed the effect of ECM condition on the pancreatic stellate cells (PSC) activation and pancreatic cancer cell migration using PANC-1 (SMAD4-WT) and BxP3 (SMAD4-null) cell lines. Notably, type I collagen induced more PSC activation than fibrin gel. Interestingly BxP3 spheroids migrated toward to the endothelial compartment compared to PANC-1. Angiogenesis of endothelial cells was more prominent in co-culture with BxP3 than PANC-1. Furthermore, we are building the metastatic model using PDAC patient derived organoids and co-culture with primary PSC in different types of ECM. Preliminary analysis showed functional responses such as 3D organoid migration and aggregation, PSC activation and migration controlled by specific properties of EMC. Our data highlight the importance of the ECM composition on PDAC migration, PSC activation and angiogenesis in the context of genetic heterogeneity and presence/absence oncogenic mutation. The 3D co-culture platform, Curiochips offers suitable and tailored solution to investigate tumor-stroma interaction and potentially can be used as a platform for drug discovery and precision oncology to target PDAC desmoplastic tumor microenvironment. Citation Format: Sumin Kim, Yeongmin Choi, Jihye Baek, Bharti Garg, Jan Pencik, Andrew M. Lowy, Herve Tiriac, Sanghee Yoo. Building a 3D co-culture model for metastatic pancreatic ductal cancer using Curiochips microphysiological system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1328.
Abstract 1659: Development of HJC0152, its analogs and protein degraders to modulate STAT3 for triple-negative breast cancer therapy
Authors: Gabrielle Vontz, Jun Li, Ruixia Ma, Jimin Xu, Mingxiang Zhou, Haiying Chen, Jia Zhou, Qiang Shen
Journal: Cancer Research (2023)

Abstract Breast cancer represents the most commonly diagnosed female malignancy worldwide. Although breast cancer screening and treatments have improved significantly over the last half-century, aggressive subtypes like triple-negative breast cancer (TNBC) as well as growing chemoresistance cases continue to evade frontline therapies. STAT3, a transcription factor involved in cell proliferation, survival, and malignant transformation, plays a key role in mammary carcinogenesis, resistance, and recurrence. Both STAT3 overexpression and aberrant activation are frequently observed in primary breast tumors and their metastatic lesions. Although STAT3 is recognized as an attractive preventive and therapeutic target, there are no FDA-approved STAT3 inhibitors in clinical use. Via structure- and fragment-based drug design strategies as well as in silico molecular modeling and docking, our team previously developed a putative STAT3 inhibitor, HJC0152. This study aims to further characterize the anticancer mechanism of HJC0152 as well as optimize its potency. Our results show that HJC0152 interacts with STAT3 with a similar specificity to an experimental STAT3 inhibitor, Stattic. To further improve its potency and efficacy, we developed several HJC0152 derivatives including HJC0152-based proteolysis targeting chimera (PROTAC) degraders. Several molecules showed comparable or improved potency to HJC0152 against several breast cancer cell lines including TNBC cells. While the total STAT3 protein level reduces moderately with HJC0152 treatment, several new compounds decrease STAT3 protein level more profoundly. In particular, the newly developed HJC0152-PROTACs showed a significant late inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues as well as a reduction in total STAT3 protein. Our data indicate that HJC0152-based analogs and protein degraders can suppress breast cancer cell proliferation, likely through targeting STAT3 signaling pathway. Future experiments will determine the molecular prolife of promising molecules as well as assess their in vivo anticancer efficacy using xenograft models. This project is supported by NIH/NCI Awards R01CA226001 and R01CA231150 to Q.S. and J.Z. Citation Format: Gabrielle Vontz, Jun Li, Ruixia Ma, Jimin Xu, Mingxiang Zhou, Haiying Chen, Jia Zhou, Qiang Shen. Development of HJC0152, its analogs and protein degraders to modulate STAT3 for triple-negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1659.